Background: As the major interface between the body and the external environment, the skin is liable to various injuries. Skin injuries often lead to severe disability, and the exploration of promising therapeutic strategies is of great importance. Exogenous mesenchymal stem cell (MSC)-based therapy is a potential strategy due to the apparent therapeutic effects, while the underlying mechanism is still elusive. Interestingly, we observed the extensive apoptosis of exogenous bone marrow mesenchymal stem cells (BMMSCs) in a short time after transplantation in mouse skin wound healing models. Considering the roles of extracellular vesicles (EVs) in intercellular communication, we hypothesized that the numerous apoptotic bodies (ABs) released during apoptosis may partially contribute to the therapeutic effects. Methods: ABs derived from MSCs were extracted, characterized, and applied in mouse skin wound healing models, and the therapeutic effects were evaluated. Then, the target cells of ABs were explored, and the effects of ABs on macrophages were investigated in vitro. Results: We found ABs derived from MSCs promoted cutaneous wound healing via triggering the polarization of macrophages towards M2 phenotype. In addition, the functional converted macrophages further enhanced the migration and proliferation abilities of fibroblasts, which together facilitated the wound healing process. Conclusions: Collectively, our study demonstrated that transplanted MSCs promoted cutaneous wound healing partially through releasing apoptotic bodies which could convert the macrophages towards an anti-inflammatory phenotype that plays a crucial role in the tissue repair process.

The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E₂ (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.

Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K–Cre–expressing (Ctsk-Cre–expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk⁺Scx⁺ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre–expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.

Intervertebral disc degeneration (IDD) results from the dysfunction of nucleus pulposus (NP) cells and the exhaustion of NP progenitors (ProNPs). The cellular applications of NP cells during IDD are currently limited due to the lack of in vivo studies showing whether NP cells are heterogeneous and contain ProNPs throughout postnatal stages. In this study, single‐cell RNA sequencing of purified NP cells is used to map four molecularly defined populations and urotensin II receptor (UTS2R)‐expressing postnatal ProNPs is identified, which are markedly exhausted during IDD, in mouse and human specimens. The lineage tracing shows that UTS2R⁺ ProNPs preferentially resides in the NP periphery with its niche factor tenascin‐C and give rise to functional NP cells. It is also demonstrated that transplanting UTS2R⁺ ProNPs with tenascin‐C into injured intervertebral discs attenuate the progression of IDD. The study provides a novel NP cell atlas, identified resident ProNPs with regenerative potential, and revealed promising diagnostic and therapeutic targets for IDD.

With the aging of the global population, the incidence of musculoskeletal diseases has been increasing, seriously affecting people's health. As people age, the microenvironment within skeleton favors bone resorption and inhibits bone formation, accompanied by bone marrow fat accumulation and multiple cellular senescence. Specifically, skeletal stem/stromal cells (SSCs) during aging tend to undergo adipogenesis rather than osteogenesis. Meanwhile, osteoblasts, as well as osteocytes, showed increased apoptosis, decreased quantity, and multiple functional limitations including impaired mechanical sensing, intercellular modulation, and exosome secretion. Also, the bone resorption function of macrophage-lineage cells (including osteoclasts and preosteoclasts) was significantly enhanced, as well as impaired vascularization and innervation. In this study, we systematically reviewed the effect of aging on bone and the within microenvironment (including skeletal cells as well as their intracellular structure variations, vascular structures, innervation, marrow fat distribution, and lymphatic system) caused by aging, and mechanisms of osteoimmune regulation of the bone environment in the aging state, and the causal relationship with multiple musculoskeletal diseases in addition with their potential therapeutic strategy.